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Targeted Agent May Improve Survival For IDH1-Mutated Advanced Cholangiocarcinoma

Advanced cholangiocarcinoma patients with an IDH1 mutation may benefit from a targeted therapy
14 Oct 2019
Anticancer Agents;  Hepatobiliary Cancers;  Personalised/Precision Medicine
By Lynda Williams, Senior medwireNews Reporter

medwireNews: ClarIDHy trial findings indicate that patients with advanced cholangiocarcinoma positive for an isocitrate dehydrogenase 1 (IDH1) mutation may benefit from treatment with ivosidenib, a small molecule inhibitor of the mutated IDH1 protein.

The phase III study results were presented at the ESMO 2019 Congress in Barcelona, Spain, by Ghassan Abou-Alfa, from Memorial Sloan-Kettering Cancer Center in New York, USA.

“These pivotal data demonstrate the clinical relevance and benefit of ivosidenib in [IDH1-mutated] cholangiocarcinoma, and establish the role for genomic testing in this rare cancer with a high unmet need”, the investigator summarised.

The ClarIDHy trial follows positive phase I findings for ivosidenib among patients with previously treated IDH1-mutated disease – a subgroup with a poor prognosis that make up to 20% of patients with cholangiocarcinoma.

Patients who had previously been given one or two prior treatments, including at least one gemcitabine- or fluorouracil-based regimen, were randomly assigned to receive ivosidenib 500 mg/day or to receive placebo, with crossover permitted at time of radiographical progression, the presenter explained.

The primary endpoint of progression-free survival (PFS) was a median of 2.7 months for the 124 ivosidenib-treated patients versus 1.4 months for the 61 placebo-treated controls, giving a significant hazard ratio (HR) of 0.37 for death or progression in favour of the targeted agent.

Six-month and 12-month rates of PFS were 32% and 22% for the ivosidenib arm versus not estimable in the controls, with 53% of ivosidenib-treated patients achieving a partial response or stable disease versus 28% of controls.

Ivosidenib efficacy was “consistent across subgroups”, said Ghassan Abou-Alfa, including when patients were considered by number of prior lines of therapy; sex; locally advanced or metastatic disease; intrahepatic or extrahepatic disease at initial diagnosis; ECOG performance score at baseline, and geographical location in North America, Europe or Asia.

Intention-to-treat analysis showed “numerically longer” median overall survival with ivosidenib than placebo, at 10.8 versus 9.7 months, although the HR of 0.69 did not reach statistical significance, despite higher OS rates at both 6 months (67 vs 59%) and 12 months (48 vs 38%).

However, OS was significantly longer with ivosidenib than placebo with a HR of 0.46 when rank-preserving structure failure time analysis was used to reconstruct the survival curve for placebo-treated patients as if they had not crossed over to ivosidenib therapy. This adjusted the median OS in the control arm to just 6.0 months, the investigator explained.

The tested dosage of ivosidenib “demonstrated a favorable safety profile”, Ghassan Abou-Alfa continued. 

Grade 3 or more severe treatment-related adverse events (TRAEs) occurred in 46.2% of ivosidenib-treated patients, including those who crossed over to the active agent, versus 35.6% of controls. Ivosidenib was associated with higher rates of grade 3 or above ascites (7.7 vs 6.8%), bilirubin elevation (5.8 vs 1.7%), anaemia (5.1 vs 0%) and aspartate transaminase (5.1 vs 1.7%).

Compared with placebo, ivosidenib was associated with higher rates of TRAEs leading to dose reductions (2.6 vs 0%) and interruptions (26.3 vs 16.9%) but a lower rate of TRAEs leading to discontinuation (5.8 vs 8.5%).

Finally, assessment of EORTC QLQ-C30 scale scores from baseline to day 1 of the second 28-day cycle of treatment suggested that ivosidenib-treated patients had less worsening of physical functioning than controls, translating to a smaller clinically meaningful decline.

This was accompanied by a lower risk of worsening emotional function and anxiety on the EORTC QLQ-C30 emotional functioning and QLQ-BIL21 anxiety symptom scores, although the presenter emphasized that the analysis is “limited by small sample size”.


Abou-Alfa GK, Maraculla T, Javle M, et al. ClarIDHy: A global, phase 3, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. ESMO 2019 Congress ; Barcelona, Spain: 27 September–1 October. LBA10_PR

Last update: 14 Oct 2019

medwireNews (www.medwireNews.com) is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group

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